Foxa2 integrates the transcriptional response of the hepatocyte to fasting

Zhang, Liping; Rubins, Nir; Ahima, Rexford S.; Greenbaum, Linda E.; Kaestner, Klaus H.

doi:10.1016/j.cmet.2005.07.002

Cited by 153 publications

(175 citation statements)

References 30 publications

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“…Indirect immunofluorescence and immunohistochemistry were performed as described previously (Zhang, Rubins, Ahima, Greenbaum & Kaestner, 2005). Slides subject to immunohistochemistry were counterstained with hematoxylin and eosin.…”

Section: Methodsmentioning

confidence: 99%

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Changes at the nuclear lamina alter binding of pioneer factor Foxa2 in aged liver

et al. 2018

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SummaryIncreasing evidence suggests that regulation of heterochromatin at the nuclear envelope underlies metabolic disease susceptibility and age‐dependent metabolic changes, but the mechanism is unknown. Here, we profile lamina‐associated domains (LADs) using lamin B1 ChIP‐Seq in young and old hepatocytes and find that, although lamin B1 resides at a large fraction of domains at both ages, a third of lamin B1‐associated regions are bound exclusively at each age in vivo. Regions occupied by lamin B1 solely in young livers are enriched for the forkhead motif, bound by Foxa pioneer factors. We also show that Foxa2 binds more sites in Zmpste24 mutant mice, a progeroid laminopathy model, similar to increased Foxa2 occupancy in old livers. Aged and Zmpste24‐deficient livers share several features, including nuclear lamina abnormalities, increased Foxa2 binding, de‐repression of PPAR‐ and LXR‐dependent gene expression, and fatty liver. In old livers, additional Foxa2 binding is correlated to loss of lamin B1 and heterochromatin (H3K9me3 occupancy) at these loci. Our observations suggest that changes at the nuclear lamina are linked to altered Foxa2 binding, enabling opening of chromatin and de‐repression of genes encoding lipid synthesis and storage targets that contribute to etiology of hepatic steatosis.

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Section: Methodsmentioning

confidence: 99%

“…Liver RNA was isolated from young and old wild‐type mice, and quantitative reverse transcription–PCR was performed as described (Zhang et al., 2005). Protein extracts preparation and protein immunoblot analysis were performed as reported previously (Bochkis et al., 2008).…”

Section: Methodsmentioning

confidence: 99%

Changes at the nuclear lamina alter binding of pioneer factor Foxa2 in aged liver

et al. 2018

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“…Post-developmentally, there are many examples of where prior binding by FoxA factors enables the subsequent binding by hormone receptors and other DNA-binding proteins (Gao et al 2003;Carroll et al 2005;Zhang et al 2005;Li et al 2009Li et al , 2012bPihlajamaa et al 2014), as previously covered in greater detail (Zaret and Carroll 2011). The mammalian circadian clock is driven by the CLOCK and BMAL1 transcription factors that rhythmically bind to nucleosomal target sites, promote incorporation of the histone variant H2A.Z, and enable the subsequent binding of other transcription factors (Menet et al 2014).…”

Section: Pioneer Factors In Cell Programming During Developmentmentioning

confidence: 99%

Pioneer transcription factors in cell reprogramming

2014

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A subset of eukaryotic transcription factors possesses the remarkable ability to reprogram one type of cell into another. The transcription factors that reprogram cell fate are invariably those that are crucial for the initial cell programming in embryonic development. To elicit cell programming or reprogramming, transcription factors must be able to engage genes that are developmentally silenced and inappropriate for expression in the original cell. Developmentally silenced genes are typically embedded in ''closed'' chromatin that is covered by nucleosomes and not hypersensitive to nuclease probes such as DNase I. Biochemical and genomic studies have shown that transcription factors with the highest reprogramming activity often have the special ability to engage their target sites on nucleosomal DNA, thus behaving as ''pioneer factors'' to initiate events in closed chromatin. Other reprogramming factors appear dependent on pioneer factors for engaging nucleosomes and closed chromatin. However, certain genomic domains in which nucleosomes are occluded by higher-order chromatin structures, such as in heterochromatin, are resistant to pioneer factor binding. Understanding the means by which pioneer factors can engage closed chromatin and how heterochromatin can prevent such binding promises to advance our ability to reprogram cell fates at will and is the topic of this review.Cell fate control represents the most extreme form of gene regulation. Genes specific to the function of a particular type of cell may be antagonistic to the function of another type of cell, so nature has evolved diverse regulatory mechanisms to ensure stable patterns of gene activation and repression. In prokaryotes, self-sustaining regulatory networks of transcription factors bound to DNA can be sufficient to regulate gene activation and repression (Ptashne 2011). In eukaryotes, ;200-base-pair (bp) segments of the genome are wound nearly twice around an octamer of the four core histones to form nucleosomes, providing steric constraints on how transcription factors can bind DNA (Kornberg and Lorch 1999). As described below, pioneer transcription factors have the special property of being able to overcome such constraints, enabling the factors to engage closed chromatin that is not accessible by other types of transcription factors (Fig. 1). However, further higher-order packaging of nucleosomes into heterochromatin can occlude access to DNA altogether, presenting an additional barrier to cell fate conversion (Fig. 1). This review focuses on the most recent studies of pioneer factors in cell programming and reprogramming, how pioneer factors have special chromatinbinding properties, and facilitators and impediments to chromatin binding. We project that such knowledge will greatly aid future efforts to change the fates of cells at will for research, diagnostic, and therapeutic purposes.

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“…3A-B. The HNF6 expression plasmids was used to synthesize 35 S-methionine-labeled HNF6 proteins via in vitro transcription and translation (Fig. 3B, right panel), which were then used for binding reactions with various GST-C/EBP␣ fusion proteins (Fig.…”

Section: Hnf6 Transcriptional Synergy Requires the C/ebp␣ Ad1/ad2 Seqmentioning

confidence: 99%

“…Furthermore, Western blot analysis demonstrated that the CBP coactivator protein Diagram of HNF6 expression plasmids containing either the full-length HNF6 protein (WT), or N-terminal HNF6 protein that deleted either the homeodomain (⌬Homeo) or the cut-homeodomain (⌬Cut-Homeo) from the C-terminus, the cut-homeodomain alone (Cut-Homeo), or the cut domain alone (Cut). These HNF6 deletion plasmids were used to synthesize radioactively labeled HNF6 proteins using in vitro transcription and translation with 35 S-methionine, which were used in the in vitro GST-C/EBP␣ pull-down assays. The right panel shows the expression of these 35 S-labeled HNF6 deletion proteins as visualized via autoradiography following SDS-PAGE.…”

Section: Hnf6 Transcriptional Synergy Requires the C/ebp␣ Ad1/ad2 Seqmentioning

confidence: 99%

C/EBPα and HNF6 protein complex formation stimulates HNF6-dependent transcription by CBP coactivator recruitment in HepG2 cells

et al. 2006

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We previously demonstrated that formation of complexes between the DNA-binding domains of hepatocyte nuclear factor 6 (HNF6) and forkhead box a2 (Foxa2) proteins stimulated Foxa2 transcriptional activity. Here, we used HepG2 cell cotransfection assays to demonstrate that HNF6 transcriptional activity was stimulated by CCAAT/enhancer-binding protein ␣ (C/EBP␣), but not by the related C/EBP␤ or C/EBP␦ proteins. Formation of the C/EBP␣-HNF6 protein complex required the HNF6 cut domain and the C/EBP␣ activation domain (AD) 1/AD2 sequences. This C/EBP␣-HNF6 transcriptional synergy required both the N-terminal HNF6 polyhistidine and serine/threonine/proline box sequences, as well as the C/EBP␣ AD1/AD2 sequences, the latter of which are known to recruit the CREB binding protein (CBP) transcriptional coactivator. Consistent with these findings, adenovirus E1A-mediated inhibition of p300/CBP histone acetyltransferase activity abrogated C/EBP␣-HNF6 transcriptional synergy in cotransfection assays. Co-immunoprecipitation assays with liver protein extracts demonstrate an association between the HNF6 and C/EBP␣ transcription factors and the CBP coactivator protein in vivo. Furthermore, chromatin immunoprecipitation assays with hepatoma cells demonstrated that increased levels of both C/EBP␣ and HNF6 proteins were required to stimulate association of these transcription factors and the CBP coactivator protein with the endogenous mouse Foxa2 promoter region. In conclusion, formation of the C/EBP␣-HNF6 protein complex stimulates recruitment of the CBP coactivator protein for expression of Foxa2, a transcription factor critical for regulating expression of hepatic gluconeogenic genes during fasting. (HEPATOLOGY 2006;43:276-286.) T ransfection studies in hepatoma cell lines demonstrated that synergistic transcriptional activation of hepatocyte-specific genes requires simultaneous binding of multiple hepatocyte nuclear factor to their promoter/enhancer regions. 1 However, the mechanisms by which these hepatocyte nuclear factor transcription factors functionally interact to elicit transcriptional synergy have yet to be deciphered. The CCAAT/enhancer Abbreviations: HNF6, hepatocyte nuclear factor 6; Foxa2, forkhead box a2; C/EBP␣, CCAAT/enhancer-binding protein

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Foxa2 integrates the transcriptional response of the hepatocyte to fasting

Cited by 153 publications

References 30 publications

Changes at the nuclear lamina alter binding of pioneer factor Foxa2 in aged liver

Changes at the nuclear lamina alter binding of pioneer factor Foxa2 in aged liver

Pioneer transcription factors in cell reprogramming

C/EBPα and HNF6 protein complex formation stimulates HNF6-dependent transcription by CBP coactivator recruitment in HepG2 cells

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